Receptor tyrosine kinase (RTK) signaling pathways are known to play a central role in tooth development. A principal pathway activated by RTKs is the Ras/Mitogen-Activated Protein Kinase (MAPK) cascade. Gain-of- function mutations in the Ras/MAPK pathway can cause a number of syndromes, termed """"""""Rasopathies"""""""". One of these syndromes is Costello Syndrome (CS), which is a rare disorder characterized by multiple craniofacial, musculoskeletal, dermatological and cardiac anomalies, as well as a varying degree of cognitive impairment and increased risk of cancer development. CS is caused by a heterozygous de novo germline mutation in HRAS that results in a constitutively active Ras protein. CS provides a unique human model to study the role of Ras signaling in craniofacial and dental development, and so my collaborators and I characterized the craniofacial and dental phenotype of CS patients. We identified a number of novel craniofacial and dental anomalies;most striking among these was a pronounced enamel hypoplasia (thinning of the enamel). Histological examination of the teeth from a CS mouse model revealed abnormal incisors with hypoplastic enamel and disorganized ameloblasts (enamel-producing cells). The ameloblasts in the CS mouse model appear to be hyperproliferative and show a loss of polarity. I propose to utilize the CS mouse model as well as in vitro CS cell models to determine the effect of activated Ras signaling on ameloblasts. Ultimately, my goal is to understand the role of Ras in amelogenesis (enamel formation) and ameloblast cell polarity. By understanding the mechanism of enamel formation, we can devise improved strategies to prevent, diagnose and treat cavities and other enamel defects. In addition, exploring the effect of Ras on ameloblast cell polarity will further reveal the general role of Ras in epithelial cell polarity.

Public Health Relevance

Enamel is the hard outer covering of teeth that protects them from decay. Enamel cannot be regenerated, and the current standard treatment of dental decay is dental restoration. By understanding how enamel forms, we can devise improved strategies to prevent, diagnose and treat cavities and other enamel defects.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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NIDCR Special Grants Review Committee (DSR)
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Frieden, Leslie A
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University of California San Francisco
Schools of Dentistry
San Francisco
United States
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Goodwin, Alice F; Oberoi, Snehlata; Landan, Maya et al. (2014) Craniofacial and dental development in Costello syndrome. Am J Med Genet A 164A:1425-30
Goodwin, Alice F; Tidyman, William E; Jheon, Andrew H et al. (2014) Abnormal Ras signaling in Costello syndrome (CS) negatively regulates enamel formation. Hum Mol Genet 23:682-92
Jones, Kyle B; Goodwin, Alice F; Landan, Maya et al. (2013) Characterization of X-linked hypohidrotic ectodermal dysplasia (XL-HED) hair and sweat gland phenotypes using phototrichogram analysis and live confocal imaging. Am J Med Genet A 161A:1585-93
Goodwin, A F; Oberoi, S; Landan, M et al. (2013) Craniofacial and dental development in cardio-facio-cutaneous syndrome: the importance of Ras signaling homeostasis. Clin Genet 83:539-44